3. SUMMARY OF THE INVENTION
The present invention relates to a method for the synthesis of a bridged fused ring pyridine of the general formula I: ##STR1## which comprises:
(A) contacting a fused ring pyridine having general formula II: ##STR2## with an unsaturated carbon bridge having the general formula III: ##STR3## in a suitable solvent comprising an amine base catalyst having a pKa of from about 11 to about 20 to form the bridged fused ring pyridine of general formula I; wherein:
R.sub.1.sup.1 is selected from the group consisting of H and C.sub.1 -C.sub.8 or branched alkoxy; PA1 R.sub.1.sup.2 is selected from the group consisting of C.sub.1 -C.sub.8 linear or branched alkyl; PA1 R.sub.2.sup.3 is selected from the group consisting of H and C.sub.1 -C.sub.8 linear or branched alkyl; PA1 R.sub.3.sup.1 is selected from the group consisting of H and C.sub.1 -C.sub.8 linear or branched alkoxy; PA1 R.sub.3.sup.2 is selected from the group consisting of C.sub.1 -C.sub.8 linear or branched alkyl; PA1 R.sub.3.sup.3 is selected from the group consisting of H and C.sub.1 -C.sub.8 linear or branched alkyl; PA1 n.sub.1 is an integer from 0 to 4; and PA1 n.sub.2 is an integer from 0 to 4; PA1 with the proviso: R.sub.1.sup.2 =R.sub.3.sup.2 ; R.sub.1.sup.1 =R.sub.3.sup.1 ; R.sub.2.sup.3 =R.sub.3.sup.3 and n.sub.1 =n.sub.2. PA1 R.sub.4.sup.4 is selected from the group consisting of H and C.sub.1 -C.sub.8 linear or branched alkyl; PA1 R.sub.4.sup.5 is selected from the group consisting of H and C.sub.1 -C.sub.8 linear or branched alkyl; PA1 R.sub.4.sup.6 is selected from the group consisting of H and C.sub.1 -C.sub.8 linear or branched alkyl; PA1 R.sub.4.sup.7 is selected from the group consisting of H and C.sub.1 -C.sub.8 linear of branched alkyl; PA1 n.sub.3 is an integer from 0 to 4; PA1 p is 0 or 1; PA1 represents a double bond between carbon 14 and 15 or a double bond between carbon 8 and 15; with the proviso: R.sub.2.sup.3 =R.sub.3.sup.3 =R.sub.4.sup.3. PA1 R.sub.1.sup.1 is selected from the group consisting of H and C.sub.1 -C.sub.8 linear or branched alkoxy; PA1 R.sub.1.sup.2 is selected from the group consisting of C.sub.1 -C.sub.8 linear or branched alkyl; PA1 R.sub.2.sup.3 is selected from the group consisting of H and C.sub.1 -C.sub.8 linear or branched alkyl; PA1 R.sub.3.sup.1 is selected from the group consisting of H and C.sub.1 -C.sub.8 linear or branched alkoxy; PA1 R.sub.3.sup.2 is selected from the group consisting of C.sub.1 -C.sub.8 linear or branched alkyl; PA1 R.sub.3.sup.3 is selected from the group consisting of H and C.sub.1 -C.sub.8 linear or branched alkyl; PA1 n.sub.1 is an integer from 0 to 4; and PA1 n.sub.2 is an integer from 0 to 4; PA1 R.sub.1.sup.1 is OCH.sub.3 ; PA1 R.sub.1.sup.2 is CH.sub.3 ; PA1 R.sub.2.sup.3 is CH.sub.3 ; PA1 R.sub.3.sup.1 is OCH.sub.3 ; PA1 R.sub.3.sup.2 is CH.sub.3 ; PA1 R.sub.3.sup.3 is CH.sub.3 ; PA1 n.sub.1 is 1; and PA1 n.sub.2 is 1. PA1 R.sub.4.sup.4 is selected from the group consisting of H and C.sub.1 -C.sub.8 linear or branched alkyl; PA1 R.sub.4.sup.5 is selected from the group consisting of H and C.sub.1 -C.sub.8 linear or branched alkyl; PA1 R.sub.4.sup.6 is selected from the group consisting of H and C.sub.1 -C.sub.8 linear or branched alkyl; PA1 R.sub.4.sup.7 is selected from the group consisting of H and C.sub.1 -C.sub.8 linear of branched alkyl; PA1 n.sub.3 is an integer from 0 to 4; PA1 p is 0 or 1; PA1 represents a double bond between carbon 14 and 15 or a double bond between carbon 8 and 15; with the proviso: R.sub.2.sup.3 =R.sub.3.sup.3 =R.sub.4.sup.3. PA1 R.sub.4.sup.3 is CH.sub.3 ; PA1 R.sub.4.sup.4 is CH.sub.3 ; PA1 R.sub.4.sup.5 is H; PA1 R.sub.4.sup.6 is H; PA1 R.sub.4.sup.7 is H; PA1 n.sub.3 is 1; PA1 p is 0 PA1 represents a double bond between carbon 8 and 15. PA1 R.sub.5.sup.3 is selected from the group consisting of H and C.sub.1 -C.sub.8 linear or branched alkyl; PA1 R.sub.5.sup.4 is selected from the group consisting of H and C.sub.1 -C.sub.8 linear or branched alkyl; PA1 R.sub.5.sup.5 selected from the group consisting of H and C.sub.1 -C.sub.8 linear or branched alkyl; PA1 R.sub.5.sup.6 is selected from the group consisting of H and C.sub.1 -C.sub.8 linear or branched alkyl; PA1 n.sub.4 is an integer from 0 to 4; PA1 p is 0 or 1; PA1 represents a double bond between carbon 14 and 15 or a double bond between carbon 8 and 15. PA1 R.sub.5.sup.1 is OCH.sub.3 ; PA1 R.sub.5.sup.3 is CH.sub.3 ; PA1 R.sub.4.sup.4 is CH.sub.3 ; PA1 R.sub.5.sup.5 is H; PA1 R.sub.5.sup.6 is H; PA1 n.sub.4 is 1; PA1 p is 0;and PA1 represents a double bond between carbon 8 and 15.
The bridged fused ring pyridine of the general formula I can be converted to the compound of general formula IV, which includes huperzine A and the analogs of huperzine A of the present invention: ##STR4## wherein: R.sub.4.sup.3 is selected from the group consisting of H and C.sub.1 -C.sub.8 linear or branched alkyl;
The compounds of general formula IV are capable of inhibiting the cholinesterase enzymes.